LXH254 是一种有效的、具有口服活性的 II 型BRAF和CRAF抑制剂,对 CRAF 和 BRAF的IC50值分别为 0.072 和 0.21 nM。
生物活性 | LXH254 is a potent, selective, orally active, type IIBRAFandCRAFinhibitor, withIC50values of 0.072 and 0.21 nM against CRAF andBRAF, respectively[2]. |
IC50& Target[1] | CRAF 0.072 nM (IC50) | Braf 0.21 nM (IC50) | ARAF 6.4 nM (IC50) | p38α 2.1 μM (IC50) | Abl1 4.9 μM (IC50) |
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体外研究 (In Vitro) | LXH254 (Compound A) is an adenosine triphosphate (ATP)-competitive inhibitor of BRAF (also referred to herein as b-RAF or b-Raf) and CRAF (also referred to herein as c-RAF or c- Raf) protein kinases. Throughout the present disclosure, LXH254 is also referred to as a c-RAF (or CRAF) inhibitor or a C-RAF/c-Raf kinase inhibitor. In cell-based assays, LXH254 has demonstrated anti-proliferative activity in cell lines that contain a variety of mutations that activate MAPK signaling. Moreover, LXH254 is a Type 2 ATP -competitive inhibitor of both B-Raf and C-Raf that keeps the kinase pocket in an inactive conformation, thereby reducing the paradoxical activation seen with many B-Raf inhibitors, and blocking mutant RAS-driven signaling and cell proliferation[1]. LXH254 (0-10 μM, 1 h) inhibits both monomeric and dimeric RAF and promotes RAF dimer formation[2]. LXH254 has reduced ability to suppress MAPK signaling driven by ARAF and further that the contribution of ARAF to MAPK signaling increases in the absence of CRAF expression[2]. LXH254 shows more sensitivity when cells lack ARAF[2].
Western Blot Analysis[2] Cell Line: | HCT116, MEL-JUSO, Mia PaCa-2, A375(BRAFV600E), and HCT116 (KRASG13D) | Concentration: | 0-10 μM | Incubation Time: | 1 h | Result: | Promoted B/CRAF heterodimer formation. Displayed similar inhibition of monomeric BRAFV600and wild-type dimeric RAF (IC50for p-ERK levels of 59 and 78 nmol/L in A-375 and HCT 116 cells, respectively). |
Cell Proliferation Assay[2] Cell Line: | Two NRAS-mutant melanoma cell lines (MEL-JUSO and SK-MEL-30), three KRAS-mutant cell lines (COR-L23, MIA PaCa-2, and HCT116), and derived variants lacking expression of either ARAF, BRAF, or CRAF. | Concentration: | 0-10 μM | Incubation Time: | 24 h | Result: | The sensitivity was increased relative to parental cell lines in all models tested by loss of ARAF expression. |
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体内研究 (In Vivo) | Treatment with LXH254 (Compound A) generates tumor regression in several KRAS-mutant models including the NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C). LXH254 exhibits efficacy in numerous MAPK-driven human cancer cell lines and in xenograft tumors representing model tumors harboring human lesions in KRAS, NRAS and BRAF oncogenes[1]. LXH254 shows significant antitumor activity in models harboring BRAF mutations either alone or coincident with either activated NRAS or KRAS, and RAS mutants lacking ARAF are more sensitive to LXH254[2].
Animal Model: | Outbred athymic (nu/nu) female mice and SCID Beige mice; BRAF-, NRAS-, and KRAS-mutant xenograft models, as well as a RAS/RAF wild-type model[2] | Dosage: | 100 mg/kg | Administration: | Orally, daily | Result: | Significantly decreased tumor volume in models harboring BRAF mutations either alone or coincident with either activated NRAS or KRAS, slightly decreased tumor volume in KRAS model. |
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运输条件 | Room temperature in continental US; may vary elsewhere. |
储存方式 | Powder | -20°C | 3 years | | 4°C | 2 years | In solvent | -80°C | 6 months | | -20°C | 1 month |
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溶解性数据 | In Vitro: DMSO : 100 mg/mL(199.01 mM;Need ultrasonic) 配制储备液 1 mM | 1.9901 mL | 9.9504 mL | 19.9009 mL | 5 mM | 0.3980 mL | 1.9901 mL | 3.9802 mL | 10 mM | 0.1990 mL | 0.9950 mL | 1.9901 mL |
*请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。 储备液的保存方式和期限:-80℃, 6 months; -20℃, 1 month。-80℃ 储存时,请在 6 个月内使用,-20℃ 储存时,请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液,再依次添加助溶剂: ——为保证实验结果的可靠性,澄清的储备液可以根据储存条件,适当保存;体内实验的工作液,建议您现用现配,当天使用;
以下溶剂前显示的百 分比是指该溶剂在您配制终溶液中的体积占比;如在配制过程中出现沉淀、析出现象,可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂: 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.5 mg/mL (4.98 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (4.98 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀;向上述体系中加入50 μL Tween-80,混合均匀;然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂: 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.5 mg/mL (4.98 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (4.98 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 2.5 mg/mL (4.98 mM); Clear solution
此方案可获得 ≥ 2.5 mg/mL (4.98 mM,饱和度未知) 的澄清溶液,此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例,取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中,混合均匀。 4. 请依序添加每种溶剂: 5% DMSO 40%PEG300 5%Tween-80 50% saline Solubility: 2.5 mg/mL (4.98 mM); Suspended solution; Need ultrasonic *以上所有助溶剂都可在本网站选购。
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